Anadu Nwanne O, Davisson V Jo, Cushman Mark
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and the Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 2006 Jun 29;49(13):3897-905. doi: 10.1021/jm0602817.
Ester derivatives of brefeldin A (BFA) were synthesized to determine which of its two hydroxyl groups could be modified while still maintaining biological activity. The compounds were tested for antiproliferative activity in the National Cancer Institute's 60 cancer cell line screen. Monoderivatization at the C4 and C7 alcohols was tolerated, yielding biologically active compounds, whereas the analogues derivatized at both positions were the least active in the series. Molecular modeling of the analogues revealed that both the C4 and C7 derivatives were well tolerated at the interface between ARF1 and its guanine nucleotide exchange factor ARNO. The Golgi-disruptive properties of the analogues were determined using fluorescence imaging assays. The BFA ester conjugates synthesized in this study were cytotoxic to cancer cells, and we have shown that the disruption of the Golgi complex is not necessary for cytotoxicity. The brefeldin A ester derivatives are potential anticancer agents.
合成布雷菲德菌素A（BFA）的酯衍生物，以确定其两个羟基中的哪一个在仍保持生物活性的同时可以被修饰。这些化合物在国立癌症研究所的60种癌细胞系筛选中测试了抗增殖活性。C4和C7醇处的单衍生化是可耐受的，产生了生物活性化合物，而在两个位置都衍生化的类似物在该系列中活性最低。类似物的分子建模表明，C4和C7衍生物在ARF1与其鸟嘌呤核苷酸交换因子ARNO之间的界面处都具有良好的耐受性。使用荧光成像测定法确定类似物的高尔基体破坏特性。本研究中合成的BFA酯缀合物对癌细胞具有细胞毒性，并且我们已经表明高尔基体复合物的破坏对于细胞毒性不是必需的。布雷菲德菌素A酯衍生物是潜在的抗癌剂。
